Journal of Leukemia

Journal of Leukemia
Open Access

ISSN: 2329-6917

+44 1300 500008

Research Article - (2016) Volume 4, Issue 2

The Utility and Applicability of Chronic Myeloid Leukemia Scoring Systems for Predicting the Prognosis of Egyptian Patients on Imatinib: Retrospective Study

Tamer A Elbedewy1* and Hossam Eldin A Elashtokhy2
1Internal Medicine Department, Faculty of Medicine, Tanta University, Egypt
2Tanta Health Insurance Hospital and Tanta Cancer Center, Egypt
*Corresponding Author: Tamer A Elbedewy, Internal Medicine Department, Faculty of Medicine, Tanta University, Egypt, Tel: 020-01151681120 Email:

Abstract

Background: Chronic myeloid leukemia (CML) is myeloproliferative clonal neoplasm. Imatinib has greatly improved CML prognosis. Many prognostic scoring systems have been developed for CML risk stratification. In clinical practice, 3 systems are widely used: Sokal, Hasford and European Treatment Outcome Study (EUTOS). Recently, EUTOS long-term survival (ELTS) score is the first long-term scoring system that considered specifically CML-related death. Therefore, the aim of the present study was to validate the effectiveness of Sokal, Hasford, EUTOS and ELTS scoring systems in predicting the outcome in Egyptian CML-chronic phase (CML-CP) patients treated with imatinib.
Patients and methods: Retrospective study performed on 167 patients with CML-CP who were treated with imatinib. Using the Sokal, Hasford, EUTOS and ELTS scores, we divided the patients into each risk groups.
Results: Significant differences in event free survival (EFS), time without progression (TWP) and overall survival (OS) prediction between the Sokal, Hasford and ELTS risk groups, but no significant difference among the EUTOS score risk groups.
Conclusion: Our study indicates that Sokal, Hasford and ELTS scoring systems but not the EUTOS score are effective in predicting early treatment response, EFS, TWP and OS for Egyptian CML patients treated with imatinib

Keywords: Chronic myeloid leukemia; Prognosis; Sokal; Hasford; EUTOS; ELTS

Introduction

Chronic myeloid leukemia (CML) is myeloproliferative clonal neoplasm with pluripotent hematopoietic stem cell origin. BCR-ABL fusion gene results from a balanced reciprocal translocation between BCR (Breakpoint cluster region) and ABL (Abelson) genes is the main finding in CML. Transposition of ABL proto-oncogene from chromosome 9 to BCR on chromosome 22 is either at chromosome level [Philadelphia (Ph) chromosome t(9;22)(q34;q11)] or cryptic at gene level. BCR-ABL encodes an unregulated, cytoplasm-targeted tyrosine kinase, leading to uninhibited cell proliferation [1,2]. CML is a triphasic disease, chronic-phase (CP), accelerated-phase (AP), and blast-phase (BP). Most patients are asymptomatic and diagnosed in CP; most patients will progress to rapidly fatal BP within 3–5 years if untreated [3].

Tyrosine kinase inhibitors (TKIs) including imatinib have greatly improved CML prognosis. In the pre TKI era, the 5-year CML overall survival (OS) with chemotherapy and interferon was 42% and 57%, respectively [4]. With imatinib the 5-year CML OS was 89–93% [5,6].

Many prognostic scoring systems have been developed for CML risk stratification. In clinical practice, 3 systems are widely used: Sokal et al. [7], Hasford et al. [8], and European Treatment Outcome Study (EUTOS) [9]. Sokal et al. [7] and Hasford et al. [8] were developed in the era of chemotherapy and interferon-α respectively. The Sokal score is based on patient age, spleen size, platelet count, and peripheral blasts % [7], and Hasford also includes peripheral eosinophil % and basophil % [8].

The Sokal and Hasford scores categorize patients as low, intermediate, or high risk and were developed to predict overall survival. In 2011, European Leukemia Network (ELN) [9] developed the European Treatment and Outcome Study (EUTOS) scoring system after doubts about the use of the 2 old systems in the TKI era to predict complete cytogenetic response (CCyR) at 18 months. EUTOS score is easy to use based only on peripheral basophil % and spleen size and categorize patients as low or high risk [10-12].

Recently, EUTOS long-term survival (ELTS) score is the first long-term scoring system that considered specifically CML-related death and categorizes patients as low, intermediate, or high risk. The authors of ELTS wrote “We hope that the ELTS score will be considered for the risk-stratified planning, analysis, and outcome interpretation of clinical trials” [13].

Therefore, the aim of the present study was to validate the effectiveness of Sokal, Hasford, EUTOS, and ELTS scoring systems in predicting the outcome in Egyptian CP-CML patients treated with imatinib.

Methods

Patients

This was a retrospective study performed on 167 patients with CML-CP selected consecutively who were treated with imatinib and diagnosed between January 2008 and December 2013 at Hematology Unit, Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta Health Insurance Hospital and other centers. The diagnosis of CML was based on characteristic peripheral blood smear and bone marrow examination findings and was confirmed by presence of Philadelphia chromosome on bone marrow cytogenetic studies or detection of BCR/ABL translocation by polymerase chain reaction (PCR) [3]. We used the previously defined diagnostic criteria for CML-CP according to ELN 2013 recommendations [14].

Treatment protocol

Imatinib mesylate (Gleevec, Novartis Pharma, Bale, Switzerland) was started at dose of 400 mg/day. The dose was adjusted according to their tolerance and response.

The patients had endured a maximum of six months from diagnosis to the imatinib treatment. Patients who received any cytoreductive treatment except for hydroxyurea and/or interferon-α (be used less than 3 months) before imatinib were excluded from the study.

Risk stratification

Sokal and Hasford scores were calculated using an online link (http://www.leukemia-net.org/content/leukemias/cml/ euro_and_sokal_score/index_eng.html). EUTOS score was also calculated using an online link (http://www.leukemia-net.org/content/ leukemias/cml/eutos_score/index_eng.html). ELTS score was also calculated using an online link (http://www.leukemia-net.org/content/ leukemias/cml/elts_score/index_eng.html). Using the Sokal, Hasford, EUTOS, and ELTS scores, we divided the patients into each risk groups. The calculation forms of each 4 scoring systems are summarized in Table 1.

Scoring system Calculation method Risk definition
Sokal et al. [7] Exp [0.0116 x (age in years - 43.4) + 0.0345 x (spleen size cm below costal margin - 7.51) + 0.188 x (platelet count⁄700)2 - 0.563) + 0.0887 x (blast cell % in peripheral blood - 2.10)] Low risk (score < 0.8)
Intermediate risk (score 0.8–1.2) High risk (score >1.2)
Hasford et al. [8] [0.666 (when age ≥ 50 years) + (0.042 x spleen size cm below costal margin) + 1.0956 (when platelet count >1500 x 109 ⁄ L) + (0.0584 x blast cell % in peripheral blood) + 0.20399 (when basophil % in peripheral blood ≥3%) + (0.0413 x eosinophil % in peripheral blood)] x 1000. Low risk (score ≤ 780) Intermediate risk (score > 780 but ≤1480)
High risk (score > 1480)
Hasford et al. [9] (7 x basophils % in peripheral blood) + (4 x spleen size cm below costal margin) Low risk ( score ≤ 87)
High risk ( score > 87 )
Pfirrmann et al. [13] 0.0025 x (age in completed years/10)3 + 0.0615 x spleen size cm below costal margin + 0.1052 x blasts % in peripheral blood + 0.4104 x (platelet count/1000)-0.5 Low-risk ( score ≤ 1.5680)
Intermediate-risk (score > 1.5680 but ≤ .2185)
High-risk (score > 2.2185)

ELTS: EUTOS Long-term Survival; EUTOS: European Treatment and Outcome Study; Exp: Exponential Function

Table 1: Method of calculation of Sokal, Hasford, EUTOS and ELTS scores.

Data collection

Data were collected by reviewing patients’ records. Records with incomplete data (nine patients) were omitted from the study. All patients’ data were handled according to ethical standards in accordance with the Declaration of Helsinki.

Follow-up

While on therapy complete blood counts were monitored weekly for the first month and then every 2 weeks thereafter till patient achieved hematological response and then monthly. BCR-ABL was done using quantitative real time- polymerase chain reaction (RT-PCR) of blood cells in our study in the most of the cases for monitoring the molecular response every 3 months. In some cases, bone marrow aspiration for cytogenetics was performed every three or six months for the first year and then every six or twelve months in the following years. Cytogenetic response was measured in bone marrow cells and determined by proportion of the Ph-positive metaphases among at least 20 metaphases analyses with R-banding technique after short-term culture and was defined as complete cytogenetic response; CCyR (Ph-positive 0%), partial cytogenetic response; PCyR (Ph-positive 1-35%), and no cytogenetic response (>35% Ph-positive). Cytogenetic response was not assessed in patients with overt hematologic progression [15].

The definitions of accelerated-phase (AP), or blast-phase (BP), complete hematologic response (CHR), major cytogenetic response (MCyR), CCyR, major molecular response (MMR) and early treatment failure were made according to ELN 2013 recommendations [14].

Complete Hematologic response (CHR) was defined as platelet count <450 × 109L, WBC count <10 × 109/L, differential without immature granulocytes, less than 5% basophils, and in addition to the disappearance of all signs and symptoms of CML including non-palpable spleen. MCyR was characterized as combination of both complete and partial cytogenetic responses. MMR was defined as BCR-ABL ≤ 0.1% in the quantitative RT-PCR of blood cells [14,16,17].

Outcomes

Different definitions, as published in previous studies, were used with minor modifications. The definition of event free survival (EFS) on the IRIS trial referred to an event as any of the following: progression to AP or BP; CML-related death; early treatment failure or loss of CHR, MCyR or MMR [5]. The definition of time without progression (TWP) by ENEST-nd referred to progression as any of the following: development of AP or BP or CML-related death [18]. Overall survival (OS) was calculated from the date of therapy initiation to the date of death or final follow up (December 2015). OS, EFS, TWP were calculated from the start of imatinib therapy.

Statistical analysis

The collected data were analyzed using SPSS version 17 software (SPSS Inc, Chicago, ILL Company). Non-parameteric data are expressed as median. Categorical variables are expressed as proportions. Fisher’s exact and Chi-square tests were used for comparison between categorical data. Cumulative Incidence of EFS, TWP and OS were estimated using Kaplan-Meier method and compared using the log rank test. The Cox regression analysis was used for multivariate analyses for factors associated with survival using the forward selection method to determine hazard ratios (HRs) and 95% confidence intervals (95% CIs). P-value ≤ 0.05 was considered statistically significant.

Results

Characteristics of the CP-CML patients

This study recruited 167 patients, with median age of 49 years (Range, 23-74) at diagnosis. There were 108 males (64.7%) and 59 females (35.3%). 109 patients (65.3%) received hydroxyurea before commencing imatinib. Other parameters at diagnosis are shown in Table 2.

Variables Range Median
Age (years) 23-74 49
Peripheral blood blast (%) 0-7 2
Peripheral blood Eosinophil (%) 0-15 2
Peripheral blood Basophil (%) 1-15 4
Platelet count (x 109/L) 152-812 341
Spleen size ( cm below the costal margin) 2-14 5
  Number %
Sex (male/female) 108/59 64.7/35.3
Sokal score ( low/ intermediate/ high) 36/95/36 21.6/56.8/21.6
Hasford score ( low/ intermediate/ high) 65/82/20 38.9/49.1/12
EUTOS score ( low/ high) 142/25 85/15
ELTS score ( low/ intermediate/ high) 76/78/13 45.5/46.7/7.8

ELTS: EUTOS Long-term Survival; EUTOS: European Treatment and Outcome Study

Table 2: Characteristics of the study population.

Sixty nine patients (41.3%) had early treatment failure with median time of 18 months (range: 3–18 months) with 95% confidence interval (14.73-17.01 months). Reasons of early treatment failure included no CHR at the 3rd month (5 patients), no cytogenetic response at the 6th month (4 patients), no complete cytogenetic response at the 12th month (4 patients), failure to achieve MMR at the 18th month (56 patients).

At the end of study; 36 patients (21.6%) died and 20 patients (12%) were lost to follow-up. 29 patients (17.4%) passed to AP, 18 of the previous 29 patients (10.8%) passed to BP up to the end of our study. 19 patients (11.4%) had MMR lose and were managed with imatinib dose escalation. All the patients were followed up for a period ranged from 26 to 81 months (median 46 months) with 95% confidence interval (45.3-49.3 months).

Sokal, Hasford, EUTOS and ELTS scores

At diagnosis, 36 (21.6%), 95 (56.8%) and 36 (21.6%) patients were in the Sokal low, intermediate and high risk groups respectively; while 65 (38.9%), 82 (49.1%) and 20 (12%) patients were in the Hasford low, intermediate and high risk groups respectively. According to the EUTOS score, 142 patients (85%) were low risk and 25 patients (15%) were high risk. 76 (45.5%), 78 (46.7%) and 13 (7.8%) patients were in the ELTS low, intermediate and high risk groups respectively (Table 2).

Comparison between Sokal, Hasford, EUTOS and ELTS risk groups as regard incidence of early treatment failure showed that higher percentages of high Sokal, Hasford and ELTS score patients and lower percentages of low Sokal, Hasford, and ELTS score patients in patients with early treatment failure when compared with patients with no early treatment failure patients. EUTOS score risk group showed insignificant differences as regard early treatment failure incidence (Table 3).

Variables Early treatment failure
No (N: 98) Yes (N: 69)
Sokal Score Low (N: 36) 29 (80.6%) 7 (19.4%)
Intermediate(N: 95) 56 (58.9%) 39 (41.1%)
High (N: 36) 13 (36.1%) 23 (63.9%)
P-value < 0.0001*
Hasford Score Low (N: 65) 54 (83.1%) 11 (16.9%)
Intermediate (N: 82) 38 (46.3%) 44 (53.7%)
High (N: 20) 6 (30%) 14 (70%)
P-value < 0.0001*
EUTOS Score Low (N: 142) 87 (61.3%) 55 (38.7%)
High (N: 25) 11 (44%) 14 (56%)
P-value 0.125
ELTS Score Low (N: 76) 62 (81.6%) 14 (18.4%)
Intermediate (N: 78) 34 (43.6%) 44 (56.4%)
High (N: 13) 2 (15.4%) 11 (84.6%)
P-value < 0.0001*

*: significant; ELTS: EUTOS Long-term Survival; EUTOS: European Treatment and Outcome Study; N: Number

Table 3: Comparison of Sokal, Hasford, EUTOS and ELTS for Early treatment failure.

Kaplan–Meier analysis

According to risk stratifications, there were significant differences in EFS, TWP and OS prediction between the Sokal, Hasford and ELTS risk groups, but insignificant difference among the EUTOS score risk groups (Table 4) (Figures 1-3).

Group (N) (%) Event free survival (EFS) Time without progression (TWP) Overall survival (OS)
Events (N) 5 years EFS (%) P-value Log rank Events (N) 5 years TWP (%) P-value Log rank Events (N) 5 years OS (%) P-value Log rank
Low Sokal score (N: 36) (21.6%) 10 65.5 <0.0001* 1 97 <0.0001* 0 100 <0.0001*
Intermediate Sokal score (N: 95) (56.8%) 49 42.4 8 85.1 9 88.5
High Sokal score (N: 36) (21.6%) 34 3.2 24 27 27 18.3
Low Hasford score (N: 65) (38.9%) 17 65.5 <0.0001* 3 93 <0.0001* 2 92.9 <0.0001*
Intermediate Hasford score (N: 82) (49.1%) 59 23.3 21 60.1 22 56.9
High Hasford score (N: 20) (12%) 17 15 9 54 12 37.9
Low EUTOS score (N: 142) (85%) 75 40 0.056 27 72.5 0.719 30 67.9 0.929
High EUTOS score (N: 25) (15%) 18 26.7 6 71.9 6 68.2
Low ELTS score (N: 76) (45.5%) 28 52.9 <0.0001* 10 79.9 0.01* 9 81.8 <0.0001*
Intermediate ELTS score (N: 78) (46.7%) 52 31 16 72.6 17 65.6
High ELTS score (N: 13) (7.8%) 13 0 33 43.5 10 26.4

*: significant; ELTS: EUTOS Long-term survival; EUTOS: European Treatment and Outcome Study; N: Number

Table 4: Event free survival (EFS), time without progression (TWP) and overall survival (OS) probability for different groups of patients.

leukemia-Kaplan–Meier

Figure 1: Kaplan–Meier analysis of the event free survival (EFS) probability.

leukemia-time-without

Figure 2: Kaplan–Meier analysis of the time without progression (TWP) probability.

leukemia-overall-survival

Figure 3: Kaplan–Meier analysis of the overall survival (OS) probability.

Our results also showed that the comparisons between every 2 subgroups in each score (Sokal, Hasford, and ELTS) for EFS, TWP, and OS had significant differences in all comparisons except (low Sokal vs. intermediate Sokal) for prediction of TWP, (intermediate Hasford vs. high Hasford) for prediction of EFS, TWP, and OS and (low ELTS vs. intermediate ELTS) for prediction of TWP and OS.

Multivariate Cox regression analysis

Multivariate Cox regression analyses were performed and showed that age (HR=1.445, 95% CI: 1.022-1.069, P<0.0001), splenic size below the costal margin (HR=1.101, 95% CI: 1.017–1.91, P=0.018), and peripheral blast % (HR=1.229, 95% CI: 1.099-1.373, P<0.0001) were independently associated with EFS. Peripheral blast % (HR=1.418, 95% CI: 1.182-1.702, P<0.0001), and platelet count (HR=1.002, 95% CI: 1.000-1.005, P=0.035) were independently associated with TWP. Peripheral blast % (HR=1.637, 95% CI: 1.345-1.992, P<0.0001) and peripheral eosinophil % (HR=1.165, 95% CI: 1.031-1.316, P=0.014) were independently associated with OS (Table 5).

Variables EFS TWP OS
HR 95% CI P-value HR 95% CI P-value HR 95% CI P-value
Age (years) 1.045 1.022-1.069 <0.0001* 1.027 0.989-1.065 0.166 1.026 0.990-1.064 0.166
Spleen size ( cm below the costal margin) 1.101 1.017-1.191 0.018* 1.014 0.889-1.158 0.831 0.957 0.840-1.090 0.505
Peripheral blood blast (%) 1.229 1.099-1.373 <0.0001* 1.418 1.182-1.702 <0.0001* 1.637 1.345-1.992 <0.0001*
Platelet count (x 109/L) 0.999 0.998-1.001 0.866 1.002 1.000-1.005 0.035* 1.001 0.999-1.004 0.205
Peripheral blood Eosinophil (%) 1.074 0.995-1.60 0.068 1.125 0.992-1.277 0.067 1.165 1.031-1.316 0.014*
Peripheral blood Basophil (%) 1.030 0.974-1.089 0.299 0.945 0.840-1.064 0.352 0.949 0.851-1.059 0.351

*: significant; CI: Confidence Interval; EFS: Event Free Survival; HR: Hazard Ratio; OS: Overall Survival; TWP: Time Without Progression

Table 5: Multivariate Cox regression analyses of clinicopathological variables and EFS, TWP, and OS.

Discussion

Therapy with TKIs is needed almost for the entire life span of CML patients, and this demands the development of new scoring system and assessment of old scoring system for risk categorization and predicting the survival and response at an early stage of CML patients. Various attempts have been made to validate the superiority of the available three old scores [12,19-21].

Identifying the right scoring system for the prognosis of patients with CP-CML undergoing imatinib therapy is controversial. Therefore, the aim of the present study was to validate the effectiveness of Sokal, Hasford, EUTOS and ELTS scoring systems in predicting the outcome in Egyptian CP-CML patients treated with imatinib.

To our knowledge, this is the first study to use data from Egyptian patients for comparing different score systems for CML prognosis and the first study to assess the ELTS score worldwide after the original paper by Pfirrmann et al. [13] who developed the ELTS score.

In our study, at diagnosis, 36 (21.6%), 95 (56.8%) and 36 (21.6%) patients were in the Sokal low, intermediate and high risk groups respectively; while 65 (38.9%), 82 (49.1%) and 20 (12%) patients were in the Hasford low, intermediate and high risk groups respectively. According to the EUTOS score, 142 patients (85%) were low risk and 25 patients (15%) were high risk. 76 (45.5%), 78 (46.7%) and 13 (7.8%) patients were in the ELTS low, intermediate and high risk groups respectively.

The percentages of different risk groups among different scoring systems had many different figures in different studies [11,13,19-32]. In Egypt, Heiba and Elshazly [22] showed that 17 (30%), 24 (43%) and 15 (27%) patients were in the Sokal low, intermediate and high risk groups respectively in a study including 56 CML-CP patients. Also in Egypt, Edesa and Abdel-malek [23] showed that the majority of the cases had low risk (75%) according to EUTOS scoring system in a study including 60 CML-CP patients. The discrepancy in the reported figures between several studies, including our study, could be due to several factors. One could be the differences in the ethnicity of the studied groups, sample size, and different age distributions in different countries.

In this study, comparison between Sokal, Hasford, EUTOS and ELTS risk groups as regard incidence of early treatment failure showed that higher percentages of high Sokal, Hasford and ELTS score patients and lower percentages of low Sokal, Hasford and ELTS score patients in patients with early treatment failure when compared with patients with no early treatment failure. EUTOS score risk group showed insignificant differences as regard early treatment failure incidence.

Also in our study, according to risk stratifications, there were significant differences in EFS, TWP and OS prediction between the Sokal, Hasford and ELTS risk groups, but insignificant difference among the EUTOS score risk groups.

Different studies had been done in patients with CML for identifying the right scoring system for the prognosis of patients with CP-CML undergoing imatinib therapy. Some of these studies were with our results and the others were against our results (Table 6). Our results are comparable and completely agreement with the following studies.

Study Country Type of study Number of patients Scores tested Drug used Result
Usman et al. [24] Pakistan Prospective 136 Sokal Imatinib Low Sokal score predict the higher hematologic as well as cytogenetic response.
de Lavallade et al. [25] United Kingdom Prospective 282 Sokal Imatinib Sokal score significantly predicted for CCyR and loss of CHR, but failed to predict for PFS and OS.
Aziz et al. [25] Pakistan Prospective 304 Sokal Imatinib Low Sokal score is significant predictive for EFS.
Marin et al. [19] United Kingdom Prospective 282 Sokal EUTOS Imatinib EUTOS score failed to predict for (OS, PFS, CCyR and MMR). Conversely, Sokal score significantly predicted for of these outcomes.
Jabbour et al. [29] United states of America Prospective 465 EUTOS Imatinib or 2nd generation TKI EUTOS score was not predictive for MMR, TFS, EFS, and OS.
Oyekunle et al. [30] Nigeria Prospective 134 Sokal Hasford Imatinib Sokal and Hasford predict significantly for PFS especially low- and intermediate-risk patients. However, neither of the scores was predictive for differences in OS or CCyR.
Hoffmann et al. [11] Several European countries Prospective 3140 EUTOS Imatinib EUTOS score was predictive for CCyR, PFS and OS.
Yamamoto et al. [27] Japan Retrospective 145 Sokal Hasford EUTOS Imatinib Sokal and Hasford Scores but not EUTOS score can predict the CCyR, EFS, PFS and OS. MMR can’t be by the 3 scores
Tao et al. [31] Chain Retrospective 220 Sokal
Hasford EUTOS
Imatinib EUTOS can predict CCyR, PFS and OS. However, Sokal and Hasford scores could not discriminate the intermediate-risk from high-risk group in either survival or CCyR.
Francis et al. [28] India Prospective 111 Sokal
Hasford EUTOS
Imatinib Sokal and Hasford scores but no EUTOS tend to influence the OS.
Xia et al. [32] Chain Retrospective 210 Sokal
Hasford EUTOS
Imatinib The 3 scoring systems were associated with EFS, PFS, and 3-month and 12-month CCyR (except EFS with EUTOS).

CCyR: Complete Cytogenetic Response; CHR: Complete Hematologic Response; EFS: Event Free Survival; EUTOS: European Treatment and Outcome Study; MMR: Major Molecular Response; OS: Overall Survival; PFS: Progression Free Survival; TFS: Transformation Free Survival; TKI: Tyrosine Kinase Inhibitor.

Table 6: Different studies for evaluation of different scoring systems for the prognosis of patients with chronic phase-chronic myeloid leukemia.

In Pakistan, Usman et al. [24] carried their study on 136 patients and found that the response was higher in patients who had low Sokal score at the time of presentation. In another study, Aziz et al. [25] carried their study on 304 patients and reported that low Sokal score was a significant predictive factor for event-free survival (EFS). In United Kingdom, de Lavallade et al. [26] found that the Sokal score can significantly predict for (OS, progression free survival (PFS), CCyR, and MMR) in 282 patients. In Japan, Yamamoto et al. [27] found in 145 CML patients that both the Sokal and Hasford scores, but not the EUTOS score, were clinically effective prognostic indicators (CCyR at 12 and 18 months, EFS, PFS and OS). In India, Francis et al. [28] who carried their study on 111 patients and found that the Sokal, Hasford but not EUTOS scoring systems were significantly associated with OS. In Egypt, Heiba and Elshazly [22] showed that Sokal score was highly significantly correlated with the response to treatment in the form of achievement of MMR at 18 months. Edesa and Abdelmalek [23] showed no statistically significant difference was observed in PFS according to EUTOS score. Marin et al. [19] and Jabbour et al. [29] evaluated the clinical significance of the EUTOS score and reported both negative findings. Pfirrmann et al. [13] showed that the ELTS score was successfully validated in an independent sample of 1120 patients. The ELTS score differentiated probabilities of dying of CML better than the Sokal, Hasford and EUTOS scores.

Other following studies had some points of agreement and some points of disagreement especially as regard the EUTOS score. In Nigeria, Oyekunle et al. [30] studied 134 CML patients and found that Sokal and Hasford risk groups predicted significantly better PFS for low- and intermediate-risk patients. However, neither of the scores was predictive for differences in OS or CCyR. In China, Tao et al. [31] made their study on 222 patients with CML and demonstrated that, EUTOS score predicted the OS, CCyR and PFS. Also, Xia et al. [32] stated that Sokal, Hasford and EUTOS scoring systems were associated with EFS, PFS, and 3-month and 12-month CCyR (except EFS with EUTOS). Using data from 3160 CML patients, Hoffmann et al. [11] recently reported that the EUTOS scoring system can predict CCyR at 18 months, PFS and OS. Also, several studies evaluated EUTOS score clinical significance and reported positive findings [12,20,21,31,32].

Our results showed that the cumulative differences between every 2 subgroups in each score (Sokal, Hasford, and ELTS) for EFS, TWP, and OS showed significant differences in all comparisons except (low Sokal vs. intermediate Sokal) for prediction of TWP, (intermediate Hasford vs. high Hasford) for prediction of EFS, TWP, and OS and (low ELTS vs. intermediate ELTS) for prediction of TWP and OS. Tao et al. [31] revealed that in the case of OS, Sokal score failed to stratify the lowand intermediate-risk groups. In the case of PFS, Sokal score could discriminate the patients of 3 risk groups significantly. Hasford score resulted in statistically significant difference between the low-risk and intermediate-risk groups in both OS and PFS, but not between the intermediate-risk and high-risk groups. The explanation of our results and the other study results are not clear and need more multicenter studies.

Our results also showed by multivariate Cox regression analyses that age, splenic size below the costal margin, and peripheral blast % were independently associated with EFS. Peripheral blast %, and platelet count were independently associated with TWP. Peripheral blast % and peripheral eosinophil %were independently associated with OS.

In comparison to the original articles which validate the original scores, Sokal et al. [7] showed in multivariate analysis that splenic size and peripheral blasts % in addition to age were the most important prognostic factors. The platelet count was only influence survival significantly when the count above 700 X 109/L. Also, Hasford et al. [8] showed in univariate and multivariate analysis age, spleen size, blasts %, basophils %, and eosinophils % correlated with survival. Hasford et al. [9] (EUTOS score) found in univariate analysis that splenic size, blasts, eosinophils, and basophils were statistically significant influence on CCyR at 18 months but the age, and platelets had no effect. Pfirrmann et al. [13] (ELTS score),showed that the cumulative incidence probabilities of CML death were significantly increased by higher age, bigger splenic size, higher peripheral blasts % and lower platelet counts.

Also, Xia et al. [32] showed that age, proportion of blasts, and platelet counts were independently associated with EFS. Age, proportion of blasts, and white blood cell count were independently associated with PFS.

The discrepancy in the reported results between several studies, including our study, could be due to several factors. One could be the differences in number and the second is ethnicity of the studied groups including environmental and genetic variations. The 3rd factor is different end points. The 4th factor is the duration of follow up.

In the present study, the EUTOS high-risk patients did not share the risk group with the other 3 scoring systems. The factors included in the Sokal, Hasford and ELTS scores are similar with small differences, but the EUTOS score includes only peripheral basophil count and the size of spleen. Age, platelet count, peripheral eosinophil and peripheral blast count, which are not included in the EUTOS score, might have a prognostic influence on CML patients.

The present study had some limitations such as, few patients were included. Also, we have not been able to objectively assess drug adherence as poor patient adherence to the CML therapy might be the predominant reason for the inability to obtain adequate molecular responses [33]. Also, this was a retrospective study with higher frequencies of biases. In general, the CML scoring systems had some limitations as, the validation of the CML risk scoring system were assessed using different end-points and the parameters used to calculate the scores, had no molecular or genetic factors.

Accordingly, further prospective, larger, multicenter, longer studies are necessary to overcome these limitations. Further studies will be required to assess the potential geographical and genetic differences between different populations as inter-racial differences in the pharmacokinetics of imatinib have been reported [34].

Conclusion

Our study indicates that Sokal, Hasford and ELTS scoring systems but not the EUTOS score are effective in predicting early treatment response, EFS, TWP and OS for Egyptian CML patients treated with imatinib.

Conflicts of Interest

The authors report no conflict of interest.

Acknowledgement

Authors would like to thank Mohamed El-Mallah (medical oncology resident, Tanta Cancer Center) for his help in collection of some materials for this study.

References

  1. Quintás-Cardama A, Cortes J (2009) Molecular biology of bcr-abl1-positive chronic myeloid leukemia. Blood 113: 1619-1630.
  2. Cortes J, O'Dwyer ME (2004) Clonal evolution in chronic myelogenous leukemia. Hematol Oncol Clin North Am 18: 671-684.
  3. Quintás-Cardama A, Cortes JE (2006) Chronic myeloid leukemia: diagnosis and treatment. Mayo Clin Proc 81: 973-988.
  4. No authors listed (1997) Interferon alfa versus chemotherapy for chronic myeloid leukemia: a meta-analysis of seven randomized trials: Chronic Myeloid Leukemia Trialists' Collaborative Group. J Natl Cancer Inst 89: 1616-1620.
  5. Druker BJ, Guilhot F, O'Brien SG, Gathmann I, Kantarjian H, et al. (2006) Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med 355: 2408-2417.
  6. Proetel U, Pletsch N, Lauseker M, Muller MC, Hanfstein B, et al (2014) Older patients with chronic myeloid leukemia (≥65 years) profit more from higher imatinib doses than younger patients: a subanalysis of the randomized CML-Study IV. Ann Hematol 93: 1167-1176.
  7. Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, et al. (1984) Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood 63: 789-799.
  8. Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, et al. (1998) A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 90: 850-858.
  9. Hasford J, Baccarani M, Hoffmann V, Guilhot J, Saussele S, et al. (2011) Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood 118: 686-692.
  10. Hoffmann V, Baccarani M, Hasford J, Guilhot J, Saussele S, et al. (2012) The EUTOS CML score aims to support clinical decision-making. Blood 119: 2966-2967.
  11. Hoffmann VS, Baccarani M, Lindoerfer D, Castagnetti F, Turkina A, et al. (2013) The EUTOS prognostic score: review and validation in 1288 patients with CML treated frontline with imatinib. Leukemia 27: 2016-2022.
  12. Uz B, Buyukasik Y, Atay H, Kelkitli E, Turgut M, et al. (2013) EUTOS CML prognostic scoring system predicts ELN-based ‘event-free survival’ better than Euro/Hasford and Sokal systems in CML patients receiving front-line ima¬tinib mesylate. Hematology 18: 247-252.
  13. Pfirrmann M, Baccarani M, Saussele S, Guilhot J, Cervantes F, et al. (2016) Prognosis of long-term survival considering disease-specific death in patients with chronic myeloid leukemia. Leukemia 30: 48-56.
  14. Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, et al. (2013) European LeukemiaNet recommendations for the management of chronic myeloid leukemia. Blood 122: 872-884.
  15. Talpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, et al. (2002) Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: result of phase 2study. Blood 99: 1928-1937.
  16. Baccarani M, Saglio G, Goldman J, Hochhaus A, Simonsson B, et al. (2006) Evolving concepts inthe management of chronic myeloid leukemia: recommendations from an expert panel on behalfof the European Leukemia Net. Blood 108: 1809-1820.
  17. Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, et al. (2009) Chronic myeloid leukemia: an update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 27: 6041-6051.
  18. Saglio G, Kim DW, Issaragrisil S, le Coutre P, Etienne G, et al. (2010) Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med 362: 2251-2259.
  19. Marin D, Ibrahim AR, Goldman JM (2011) European Treatment and Outcome Study (EUTOS) score for chronic myeloid leukemia still requires more confirmation. J Clin Oncol 29: 3944-3945.
  20. Yahng SA, Jang EJ, Choi SY, Oh YJ, Bang JH, et al. (2012) Comparison of Sokal, Hasford and EUTOS scores in terms of long-term treatment outcome according to the risks in each prognostic model: a single center data analyzed in 255 early chronic phase chronic myeloid leukemia patients treated with frontline imatinib mesylate. Blood 120: Abstract 2794.
  21. Yahng SA, Jang EJ, Choi SY, Lee SE, Kim SH, et al. (2014) Prognostic discrimination for early chronic phase chronic myeloid leukemia in imatinib era: comparison of Sokal, Euro, and EUTOS scores in Korean population. Int J Hematol 100: 132-140.
  22. Heiba NM, Elshazly SA (2013) SHP-1 expression in chronic myeloid leukemia: clinical significance and impact on response to imatinib treatment. Egypt J Haematol 38: 84-89.
  23. Edesa WA, Abdel-malek RR (2015) Impact of imatinib interruption and duration of prior hydroxyurea on the treatment outcome in patients with chronic myeloid leukemia: Single institution experience. J Egypt Natl Canc Inst 27: 69-75.
  24. Usman M, Syed NN, Kakepoto GN, Adil SN, Khurshid M (2007) Chronic phase chronic myeloid leukemia: response of imatinib mesylate and significance of Sokal score, age and disease duration in predicting the hematological and cytogenetic response. J Assoc Physicians India 55: 103-107.
  25. Aziz Z, Iqbal J, Bano K, Faisal M, Akram M (2010) Sustained superior long-term outcomes and cytogenetic responses with imatinib mesylate in chronic phase chronic myeloid leukaemia: report from a developing country. Jpn J Clin Oncol 40: 549-555.
  26. de Lavallade H, Apperley JF, Khorashad JS, Milojkovic D, Reid AG, et al. (2008) Imatinib for newly diagnosed patients with chronic myeloid leukemia: incidence of sustained responses in an intention-to-treat analysis. J Clin Oncol 26: 3358-3363.
  27. Yamamoto E, Fujisawa S, Hagihara M, Tanaka M, Fujimaki K, et al. (2014) European Treatment and Outcome Study score does not predict imatinib treatment response and outcome in chronic myeloid leukemia patients. Cancer Sci 105: 105-109.
  28. Francis J, Dubashi B, Sundaram R, Pradhan SC, Chandrasekaran A (2015) Influence of Sokal, Hasford, EUTOS scores and pharmacogenetic factors on the complete cytogenetic response at 1 year in chronic myeloid leukemia patients treated with imatinib. Med Oncol 32: 213.
  29. Jabbour E, Cortes J, Nazha A, O'Brien S, Quintas-Cardama A, et al. (2012) EUTOS score is not predictive for survival and outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors: a single institution experience. Blood 119: 4524-4526.
  30. Oyekunle AA, Osho PO, Aneke JC, Salawu L, Durosinmi MA (2012) The predictive value of the Sokal and Hasford scoring systems in chronic myeloid leukaemia in the imatinib era. Journal of Hematological Malignancies 2: 25-32.
  31. Tao Z, Liu B, Zhao Y, Wang Y, Zhang R, et al. (2014) EUTOS score predicts survival and cytogenetic response in patients with chronic phase chronic myeloid leukemia treated with first-line imatinib. Leuk Res 38: 1030-1035.
  32. Xia L, Qian W, Yang M, Li Q, Liu F, et al. (2015) Comparison of the utility and applicability of the Sokal, Hasford, and EUTOS scores in a population of Chinese patients with chronic-phase chronic myeloid leukemia undergoing imatinib therapy. Onco Targets Ther 8: 2485-2492.
  33. Marin D, Bazeos A, Mahon FX, Eliasson L, Milojkovic D, et al. (2010) Adherence is the critical factor for achieving molecular response in patients with chronic myeloid leukemia who achieve complete cytogenic response on imatinib. J Clin Oncol 28: 2381-2388.
  34. Singh O, Chan JY, Lin K, Heng CC, Chowbay B (2012) SLC22A1-ABCB1 haplotype profiles predict imatinib pharmacokinetics in Asian patients with chronic myeloid leukemia. PLoS One 7: e51771.
Citation: Elbedewy TA, Elashtokhy HE (2016) The Utility and Applicability of Chronic Myeloid Leukemia Scoring Systems for Predicting the Prognosis of Egyptian Patients on Imatinib: Retrospective Study. J Leuk 4:210.

Copyright: © 2016 Elbedewy TA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Top